{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T05:47:26Z","timestamp":1789624046160,"version":"build-2803163510"},"reference-count":30,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2017,11,16]],"date-time":"2017-11-16T00:00:00Z","timestamp":1510790400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Mundipharma Research Ltd, Cambridge, UK"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Addiction"],"published-print":{"date-parts":[[2018,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and Aims<\/jats:title><jats:p>Take\u2010home naloxone can prevent death from heroin\/opioid overdose, but pre\u2010provision is difficult because naloxone is usually given by injection. Non\u2010injectable alternatives, including naloxone nasal sprays, are currently being developed. To be effective, the intranasal (i.n.) spray dose must be adequate but not excessive, and early absorption must be comparable to intramuscular (i.m.) injection. We report on the pharmacokinetics (PK) of a specially produced concentrated novel nasal spray. The specific aims were to: (1) estimate PK profiles of i.n. naloxone, (2) compare early systemic exposure with i.n. versus i.m. naloxone and (3) estimate i.n. bioavailability.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design<\/jats:title><jats:p>Open\u2010label, randomized, five\u2010way cross\u2010over PK study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Setting<\/jats:title><jats:p>Clinical trials facility (Croydon, UK).<\/jats:p><\/jats:sec><jats:sec><jats:title>Participants<\/jats:title><jats:p>Thirty\u2010eight healthy volunteers (age 20\u201354\u00a0years; 11 female).<\/jats:p><\/jats:sec><jats:sec><jats:title>Intervention and comparator<\/jats:title><jats:p>Three doses of i.n. (1\u00a0mg\/0.1\u00a0ml, 2\u00a0mg\/0.1\u00a0ml, 4\u00a0mg\/0.2\u00a0ml) versus 0.4\u00a0mg i.m. (reference) and 0.4\u00a0mg intravenous (i.v.) naloxone.<\/jats:p><\/jats:sec><jats:sec><jats:title>Measurements<\/jats:title><jats:p>Regular blood samples were taken, with high\u2010frequency sampling during the first 15\u00a0minutes to capture early systemic exposure. PK parameters were determined from plasma naloxone concentrations. Exploratory analyses involved simulation of repeat administration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Findings<\/jats:title><jats:p>Mean peak concentration (C<jats:sub>max<\/jats:sub>) values for 1\u00a0mg (1.51\u00a0ng\/ml), 2\u00a0mg (2.87\u00a0ng\/ml) and 4\u00a0mg (6.02\u00a0ng\/ml) i.n. exceeded 0.4\u00a0mg i.m. (1.27\u00a0ng\/ml) naloxone. All three i.n. doses rapidly achieved plasma levels &gt;\u00a050% of peak concentrations (T50%) by 10\u00a0minutes, peaking at 15\u201330\u00a0minutes (T<jats:sub>max<\/jats:sub>). For comparison, the i.m. reference reached T<jats:sub>max<\/jats:sub> at 10\u00a0minutes. Mean bioavailability was 47\u201351% for i.n. relative to i.m. naloxone. Simulation of repeat dosing (2\u00a0\u00d7\u00a02\u00a0mg i.n. versus 5\u00a0\u00d7\u00a00.4\u00a0mg i.m. doses) at 3\u2010minute intervals showed that comparable plasma naloxone concentrations would be anticipated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Concentrated 2\u00a0mg intranasal naloxone is well\u2010absorbed and provides early exposure comparable to 0.4\u00a0mg intramuscular naloxone, following the 0.4\u00a0mg intramuscular curve closely in the first 10\u00a0minutes post\u2010dosing and maintaining blood levels above twice the intramuscular reference for the next 2 hours.<\/jats:p><\/jats:sec>","DOI":"10.1111\/add.14033","type":"journal-article","created":{"date-parts":[[2017,11,16]],"date-time":"2017-11-16T09:02:36Z","timestamp":1510822956000},"page":"484-493","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":90,"title":["Pharmacokinetics of concentrated naloxone nasal spray for opioid overdose reversal: Phase I healthy volunteer study"],"prefix":"10.1111","volume":"113","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3373-4943","authenticated-orcid":false,"given":"Rebecca","family":"McDonald","sequence":"first","affiliation":[{"name":"National Addiction Centre, Institute of Psychiatry, Psychology and Neuroscience King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Lorch","sequence":"additional","affiliation":[{"name":"Richmond Pharmacology Ltd Croydon University Hospital (Woodcroft Wing)  Croydon UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo","family":"Woodward","sequence":"additional","affiliation":[{"name":"Mundipharma Research Ltd Cambridge Science Park  Cambridgeshire UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Bosse","sequence":"additional","affiliation":[{"name":"Mundipharma Research GmbH and Co. KG  Limburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Dooner","sequence":"additional","affiliation":[{"name":"Mundipharma Research Ltd Cambridge Science Park  Cambridgeshire UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gill","family":"Mundin","sequence":"additional","affiliation":[{"name":"Mundipharma Research Ltd Cambridge Science Park  Cambridgeshire UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Smith","sequence":"additional","affiliation":[{"name":"Mundipharma Research Ltd Cambridge Science Park  Cambridgeshire UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Strang","sequence":"additional","affiliation":[{"name":"National Addiction Centre, Institute of Psychiatry, Psychology and Neuroscience King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,11,16]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"United Nations Office on Drugs and Crime (UNODC).World Drug Report.2016. Available at:https:\/\/www.unodc.org\/wdr2016\/(accessed 1 December 2016) (Archived athttp:\/\/www.webcitation.org\/6u56T1R41on 9 October 2017)."},{"key":"e_1_2_9_3_1","unstructured":"World Health Organization (WHO).Community Management of Opioid Overdose 2014. Available at:http:\/\/apps.who.int\/iris\/bitstream\/10665\/137462\/1\/9789241548816_eng.pdf?ua=1&ua=1(accessed 25 January 2016) (Archived athttp:\/\/www.webcitation.org\/6qHBtnGWjon 7 May 2017)."},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1360-0443.1999.9421993.x"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.2105\/AJPH.2008.146647"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/add.13209"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/add.13267"},{"key":"e_1_2_9_8_1","volume-title":"Naloxone for Outpatient Use: Data Required to Support an NDA","author":"Hertz S.","year":"2012"},{"key":"e_1_2_9_9_1","unstructured":"United Nations Office on Drugs and Crime\/World Health Organization (UNODC\/WHO).Opioid overdose: preventing and reducing opioid overdose mortality Vienna: United Nations 2013. Available at:http:\/\/www.unodc.org\/docs\/treatment\/overdose.pdf(accessed 10 March 2016) (Archived athttp:\/\/www.webcitation.org\/6qH7oiNbNon 7 May 2017)."},{"key":"e_1_2_9_10_1","unstructured":"Adapt.NARCAN\u00ae(naloxone hydrochloride) nasal spray\u2014patient information leaflet 2015. Available at:http:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2015\/208411lbl.pdf(accessed 4 April 2016) (Archived athttp:\/\/www.webcitation.org\/6qHAYi0jQon 7 May 2017)."},{"key":"e_1_2_9_11_1","unstructured":"Food and Drug Administration(FDA).FDA moves quickly to approve easy\u2010to\u2010use nasal spray to treat opioid overdose 2015. Available at:http:\/\/www.fda.gov\/NewsEvents\/Newsroom\/PressAnnouncements\/ucm473505.htm(accessed 18 March 2016) (Archived athttp:\/\/www.webcitation.org\/6qH9DSNq5on 7 May 2017)."},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.759"},{"key":"e_1_2_9_13_1","unstructured":"CBC News.Health Canada OK's non\u2010prescription nasal spray overdose antidote 2016. Available at:http:\/\/www.cbc.ca\/news\/health\/naloxone\u2010nasal\u2010spray\u20101.3789643(accessed 5 October 2016) (Archived athttp:\/\/www.webcitation.org\/6qH9uGq0Ron 7 May 2017)."},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/add.13849"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0b013e3181816214"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/add.13027"},{"key":"e_1_2_9_17_1","unstructured":"UK Medicines Information (UKMi).Naloxone products for emergency opiate overdose reversal in non\u2010medical settings 2016. 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